Loss of Interleukin–18 Negative–Feedback Associated with Severity and Mortality in Prospective Cohort Study of 206 Hospitalised COVID–19 Patients

Abstract Background: Divergence between deterioration to life–threatening COVID–19 or clinical improvement occurs for most within the first 14 days of symptoms. Life–threatening COVID–19 shares clinical similarities with Macrophage Activation Syndrome, which can be driven by elevated Free Interleukin–18 (IL–18) due to failure of negative-feedback release of IL–18 binding protein (IL–18bp). We therefore designed a prospective, longitudinal cohort study to examine IL–18 negative–feedback control in relation to COVID–19 severity and mortality from symptom day 15 onwards. Methods: 662 blood samples, matched to time from symptom onset, from 206 COVID–19 patients were analysed by enzyme–linked immunosorbent assay for IL–18 and IL–18bp, enabling calculation of free IL–18 (fIL–18) using the updated dissociation constant (Kd) of 0.05 nanomoles. Adjusted multivariate regression analysis was used to assess the relationship between highest fIL–18 and outcome measures of COVID-19 severity and mortality. Results: Up to symptom day 14, mean fIL–18 levels increase in all patients. Levels in survivors declined thereafter, but remained elevated in non–survivors, due to IL–18 production without commensurate IL–18bp release. Adjusted regression analysis from symptom day 15 onwards showed a 100 mmHg decrease in Pa02/Fi02 (primary outcome) for each 37.7 pg/ml increase in highest fIL–18 (p < 0.03). Per 50 pg/ml increase in highest fIL–18, adjusted logistic regression gave an odds–ratio (OR) for crude 60–day mortality of 1.41 (1.1 – 2.0) (p < 0.03), and an OR for death with hypoxaemic respiratory failure of 1.90 [1.3 – 3.1] (p < 0.01). Highest fIL–18 was associated also with organ failure, with an increase of 63.67 pg/ml for every additional organ supported (p < 0.01) in patients with hypoxaemic respiratory failure. In this same sub-group, highest fIL–18 showed a direct correlation with Neutrophil/Lymphocyte ratio, with an increase in fIL–18 by 3.54 pg/ml (p < 0.03) for each unit increase. Conclusions: Loss of IL–18 negative–feedback control, from symptom day 15 onwards is associated with COVID–19 severity and mortality. ISRCTN: #13450549; registration date: 30/12/2020.